CN114848604A - Empagliflozin and metformin hydrochloride compound preparation and preparation method thereof - Google Patents
Empagliflozin and metformin hydrochloride compound preparation and preparation method thereof Download PDFInfo
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- CN114848604A CN114848604A CN202210661762.0A CN202210661762A CN114848604A CN 114848604 A CN114848604 A CN 114848604A CN 202210661762 A CN202210661762 A CN 202210661762A CN 114848604 A CN114848604 A CN 114848604A
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- Prior art keywords
- empagliflozin
- metformin hydrochloride
- hydrochloride
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 90
- 229960004329 metformin hydrochloride Drugs 0.000 title claims abstract description 87
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 title claims abstract description 77
- 229960003345 empagliflozin Drugs 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- -1 metformin hydrochloride compound Chemical class 0.000 title abstract description 8
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims abstract description 80
- 239000002245 particle Substances 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 239000008187 granular material Substances 0.000 claims abstract description 29
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960000540 polacrilin potassium Drugs 0.000 claims abstract description 16
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 claims abstract description 16
- 239000003085 diluting agent Substances 0.000 claims abstract description 12
- 239000007884 disintegrant Substances 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 239000011230 binding agent Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 16
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 11
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 10
- 239000000853 adhesive Substances 0.000 claims description 10
- 230000001070 adhesive effect Effects 0.000 claims description 10
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 10
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 10
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 229940069328 povidone Drugs 0.000 claims description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 235000010356 sorbitol Nutrition 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 3
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229960003105 metformin Drugs 0.000 claims description 2
- 229940032147 starch Drugs 0.000 claims description 2
- 238000005550 wet granulation Methods 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims 1
- 235000019700 dicalcium phosphate Nutrition 0.000 claims 1
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- VQUPQWGKORWZII-WDPYGAQVSA-N (2r,3r)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3-[(2s,3r,4r,5r,6s)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy-2,3-dihydrochromen-4-one Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1C(=O)C2=C(O)C=C(O)C=C2O[C@@H]1C1=CC=C(O)C=C1 VQUPQWGKORWZII-WDPYGAQVSA-N 0.000 description 4
- VQUPQWGKORWZII-KTLFEHCLSA-N Dihydrokaempferol-3-O-alpha-L-rhamnopyranoside Natural products O([C@@H]1[C@H](c2ccc(O)cc2)Oc2c(c(O)cc(O)c2)C1=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O1 VQUPQWGKORWZII-KTLFEHCLSA-N 0.000 description 4
- VQUPQWGKORWZII-UHFFFAOYSA-N Neoisoengelitin Natural products OC1C(O)C(O)C(C)OC1OC1C(=O)C2=C(O)C=C(O)C=C2OC1C1=CC=C(O)C=C1 VQUPQWGKORWZII-UHFFFAOYSA-N 0.000 description 4
- 229960005455 polacrilin Drugs 0.000 description 4
- 229960002920 sorbitol Drugs 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000002641 glycemic effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940002735 empagliflozin / metformin Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 229940002737 synjardy Drugs 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an engelet and metformin hydrochloride compound preparation and a preparation method thereof, wherein the compound preparation comprises engelet particles and metformin hydrochloride particles; the engelet granules comprise engelet, polacrilin potassium, maltose-cyclodextrin, a disintegrating agent and a binding agent; the metformin hydrochloride granules comprise metformin hydrochloride, a diluent, a disintegrant and a binder; wherein the particle size d0.9 of the empagliflozin is not more than 30 μm. The compound preparation can solve the problem that the content uniformity is not easy to control due to the great difference between the dosage of the empagliflozin hydrochloride and the dosage of the metformin hydrochloride; meanwhile, the problem of poor solubility of the empagliflozin can be effectively solved, and the effect that the dissolution curves of the empagliflozin and the metformin hydrochloride are consistent with those of the original products on the market is realized.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an empagliflozin and metformin hydrochloride compound preparation and a preparation method thereof.
Background
The engeletin as an SGLT-2 inhibitor drug is proved to block the reabsorption of glucose in the kidney and excrete excessive glucose to the outside of the body, thereby achieving the effect of reducing the blood sugar level, and the blood sugar reducing effect is independent of beta cell function and insulin resistance. Compared with placebo, empagliflozin, in addition to being effective in lowering blood glucose, also contributes to weight loss and blood pressure reduction. Clinically, empagliflozin is used to improve glycemic control in type 2 diabetic patients. The empagliflozin can be used in combination with metformin hydrochloride to improve glycemic control in type 2 diabetic patients on a dietary and exercise basis. The engeletin/metformin hydrochloride tablet is a compound preparation developed by the company Boringer Vargahan for treating diabetes. On 5 months 2015, the european union approved the application for the marketing of empagliflozin/metformin hydrochloride. In 2015, 8 months, the compound of empagliflozin hydrochloride is approved by FDA to be marketed.
The name of the engelia purification theory is: (1S) -1, 5-anhydro-1- (4-chloro-3- {4- [ (3S) -tetrahydrofuran-3-oxy ] benzyl } phenyl ] -D-glucitol having the formula:
engagliflozin is white to light yellow, a hygroscopic powder. Very slightly soluble in water, poorly soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% acetonitrile in water, and practically insoluble in toluene. The solubility of the empagliflozin is low, and the metformin hydrochloride is easily dissolved in water; in addition, in the marketed compound formulation of Empagliflozin hydrochloride, the dosage of metformin hydrochloride in unit formulation is 500-1000mg, the dosage of Empagliflozin is 5-12.5mg, the dosage difference between the Empagliflozin hydrochloride and the Empagliflozin hydrochloride is very large, the problem of poor content uniformity is easily caused because the Empaglozin hydrochloride and the Empagliflozin hydrochloride cannot be completely mixed. In actual production, how to rapidly dissolve the empagliflozin and the metformin hydrochloride in the empagliflozin and metformin hydrochloride compound preparation and have better content uniformity still has great challenge.
Therefore, how to solve the problems of poor content uniformity and poor Empagliflozin solubility caused by great dosage variation of medicinal components is a problem to be solved currently.
Disclosure of Invention
In view of the above, the invention provides an englezin and metformin hydrochloride compound preparation, which can solve the problem that the content uniformity is not easy to control due to the great difference of the use amounts of the englezin and the metformin hydrochloride, and obtain a compound preparation with uniform content; meanwhile, the problem of poor solubility of the empagliflozin can be effectively solved, the empagliflozin can be quickly dissolved out, and the effect that the dissolution curve of the empagliflozin and the metformin hydrochloride is consistent with that of the original product on the market is realized. The invention also provides a method for preparing the compound preparation of the empagliflozin hydrochloride and the metformin hydrochloride, which is simple and easy to operate, can meet the production requirements by conventional equipment, has controllable quality and is suitable for industrial large-scale production.
The invention provides an empagliflozin and metformin hydrochloride compound preparation, which comprises empagliflozin particles and metformin hydrochloride particles; the engelet granules comprise engelet, polacrilin potassium, maltose-cyclodextrin, a disintegrating agent and a binding agent; the metformin hydrochloride granules comprise metformin hydrochloride, a diluent, a disintegrant and a binder; wherein the particle size d0.9 of the empagliflozin is not more than 30 μm.
In order to solve the problem that the dosage difference between the empagliflozin hydrochloride and the metformin hydrochloride is great, the empagliflozin hydrochloride and the metformin hydrochloride are respectively prepared into granules, and the empagliflozin hydrochloride and metformin hydrochloride compound preparation has good content uniformity. In addition, because the solubility of the empagliflozin is poor, in order to ensure that the empagliflozin and the metformin hydrochloride are quickly dissolved out, the particle size d0.9 of the empagliflozin is controlled to be not more than 30 mu m, the potassium polacrilin and the maltose-cyclodextrin are added into empagliflozin particles, the dissolution of the empagliflozin can be well promoted through the particle size control of the empagliflozin and the coordination of the potassium polacrilin and the maltose-cyclodextrin, and the problem of poor solubility of the empagliflozin is solved.
In the compound preparation of the empagliflozin and the metformin hydrochloride, the particle size d0.9 of the empagliflozin is preferably 8-30 μm.
In order to better control the dissolution of the empagliflozin, the dosage of the polacrilin potassium and the maltose-cyclodextrin in the empagliflozin particles is considered, and the mass dosage ratio of the polacrilin potassium to the maltose-cyclodextrin is 1-5: 1.
In the compound preparation of engeletin and metformin hydrochloride, the disintegrant is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium.
In the compound preparation of the empagliflozin and the metformin hydrochloride, the adhesive is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and povidone.
In the compound preparation of the empagliflozin and the metformin hydrochloride, the empagliflozin particles also comprise a diluent.
In the compound preparation of the empagliflozin and the metformin hydrochloride, the diluent is one or more of microcrystalline cellulose, pregelatinized starch, lactose, calcium hydrophosphate, sorbitol, starch and sucrose.
In the compound preparation of the empagliflozin and the metformin hydrochloride, the empagliflozin particles and/or the metformin hydrochloride particles also comprise a lubricant.
In the compound preparation of the engeletin and the metformin hydrochloride, the lubricant is one or more of magnesium stearate, aerosil and talcum powder.
In the compound preparation of the empagliflozin and the metformin hydrochloride, the compound preparation comprises the following components in parts by mass:
the engelet granule comprises 5-12.5 parts of engelet, 30-70 parts of polacrilin potassium, 10-30 parts of maltose-cyclodextrin, 2-5 parts of disintegrant and 2-5 parts of adhesive;
the metformin hydrochloride particles comprise 1000 parts of metformin hydrochloride 500-plus, 24-50 parts of diluent, 20-50 parts of disintegrant and 6-18 parts of adhesive;
wherein the dosage of the metformin hydrochloride is calculated by metformin.
The invention also provides a preparation method of the compound preparation of the empagliflozin and the metformin hydrochloride, which comprises the following steps:
(1) uniformly mixing the engletin, the polacrilin potassium, the maltose-cyclodextrin, the disintegrating agent and the adhesive, granulating by a wet method, and drying to obtain engletin granules;
(2) uniformly mixing metformin hydrochloride, a diluent, a disintegrating agent and an adhesive, performing wet granulation, and drying to obtain metformin hydrochloride granules;
(3) the empagliflozin particles and the metformin hydrochloride particles are uniformly mixed and tabletted.
In the preparation method of the compound preparation of the empagliflozin hydrochloride and the metformin hydrochloride, the step (1) also comprises the step of adding a diluent and/or a lubricant; the step (2) further comprises a step of adding a lubricant.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention limits the particle diameter d0.9 of the Engelliflozin not more than 30 mu m in the Engelliflozin particles, adds the auxiliary materials of the polacrilin potassium and the maltose-cyclodextrin in the prescription, and is matched with the disintegrating agent and the adhesive, thereby being capable of promoting the rapid dissolution of the Engelliflozin.
2. The invention respectively prepares the englezin and the metformin hydrochloride into granules, and then mixes and tabletting, thereby well solving the problem that the content uniformity is difficult to control due to great difference of the usage amount of the englezin and the metformin hydrochloride.
Detailed Description
Example 1
Engeletyn d0.9 ═ 18 μm.
The preparation method comprises the following steps:
(1) uniformly mixing the engagliflozin, potassium polacrilin, maltose-cyclodextrin, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, granulating by a wet method, and drying to obtain engagliflozin particles;
(2) uniformly mixing metformin hydrochloride, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, granulating by a wet method, and drying to obtain metformin hydrochloride granules;
(3) the empagliflozin particles and the metformin hydrochloride particles are uniformly mixed and tabletted.
Example 2
Engeletyn d0.9 ═ 20 μm.
The preparation method comprises the following steps:
(1) uniformly mixing the engletin, the polacrilin potassium, the maltose-cyclodextrin, the crospovidone and the hydroxypropyl methyl cellulose, granulating by a wet method, and drying to obtain engletin granules;
(2) uniformly mixing metformin hydrochloride, pregelatinized starch, sorbitol, sodium carboxymethyl starch and hydroxypropyl cellulose, granulating by a wet method, and drying to obtain metformin hydrochloride granules;
(3) the empagliflozin particles and the metformin hydrochloride particles are uniformly mixed and tabletted.
Example 3
Engeletyn d0.9 ═ 30 μm.
The preparation method comprises the following steps:
(1) uniformly mixing the engletin, the polacrilin potassium, the maltose-cyclodextrin, the low-substituted hydroxypropyl cellulose, the sodium carboxymethylcellulose and the lactose, granulating by a wet method, and drying to obtain engletin granules;
(2) uniformly mixing metformin hydrochloride, calcium hydrophosphate, starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and hydroxypropyl cellulose, granulating by a wet method, and drying to obtain metformin hydrochloride granules;
(3) the engagliflozin hydrochloride granules, the metformin hydrochloride granules and the magnesium stearate are uniformly mixed and tabletted.
Example 4
Engeletyn d0.9 ═ 12 μm.
The preparation method comprises the following steps:
(1) uniformly mixing the engagliflozin, the polacrilin potassium, the maltose-cyclodextrin, the low-substituted hydroxypropyl cellulose, the povidone and the micropowder silica gel, granulating by a wet method, and drying to obtain engagliflozin granules;
(2) uniformly mixing metformin hydrochloride, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, povidone and talcum powder, granulating by a wet method, and drying to obtain metformin hydrochloride granules;
(3) the empagliflozin particles and the metformin hydrochloride particles are uniformly mixed and tabletted.
Example 5
Engeletyn d0.9 ═ 10 μm.
The preparation method comprises the following steps:
(1) uniformly mixing the engrel, the polacrilin potassium, the maltose-cyclodextrin, the sodium carboxymethyl starch, the low-substituted hydroxypropyl cellulose, the hydroxypropyl cellulose and the magnesium stearate, granulating by a wet method, and drying to obtain engrel granules;
(2) uniformly mixing metformin hydrochloride, microcrystalline cellulose, sorbitol, low-substituted hydroxypropyl cellulose and hydroxypropyl cellulose, granulating by a wet method, and drying to obtain metformin hydrochloride granules;
(3) the empagliflozin particles and the metformin hydrochloride particles are uniformly mixed and tabletted.
Example 6
Engeletyn d0.9 ═ 8 μm.
The preparation method comprises the following steps:
(1) uniformly mixing the engletin, the polacrilin potassium, the maltose-cyclodextrin, the croscarmellose sodium and the povidone, granulating by a wet method, and drying to obtain the engletin granules;
(2) uniformly mixing metformin hydrochloride, microcrystalline cellulose, sucrose, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose and superfine silica gel powder, granulating by a wet method, and drying to obtain metformin hydrochloride granules;
(3) the engagliflozin hydrochloride granules, the metformin hydrochloride granules and the magnesium stearate are uniformly mixed and tabletted.
Comparative example
The preparation method is the same as example 1.
Test for content uniformity
The content uniformity of engletin in the samples obtained in the examples and in the commercial products (trade name Synjardy; specification: 5mg/500mg in terms of engletin, metformin hydrochloride) was determined by HPLC, and the results were as follows:
according to the invention, the content uniformity of the empagliflozin with a small dosage is investigated, and the experimental data show that the empagliflozin of the sample prepared according to the invention has good content uniformity and conforms to the regulations of Chinese pharmacopoeia.
Examination of dissolution
Taking samples obtained in examples and comparative examples and commercial products, according to the dissolution and dissolution determination method of four 9031 parts of China pharmacopoeia 2020 edition, taking phosphate buffer solution with pH6.8 as dissolution medium, rotating speed is 75rpm per minute, and dissolution (%) of empagliflozin hydrochloride and metformin hydrochloride is determined at 5min, 10min, 15min, 20min and 30 min. The results obtained were as follows:
from the experimental data, the potassium bolacrine and the maltose-cyclodextrin are added in the embodiment of the invention, and the particle size d0.9 of the empagliflozin is controlled to be not more than 30 μm, so that the empagliflozin can be promoted to dissolve, and the effect that the dissolution curves of the empagliflozin and the metformin hydrochloride are consistent with those of the original products on the market in the grinding is obtained. In contrast, in comparative example 1, hydroxypropyl-beta-cyclodextrin is used instead of maltose-cyclodextrin, in comparative examples 2 to 3, potassium polacrilin and maltose-cyclodextrin are not simultaneously contained, and in comparative example 4, the particle size d0.9 of the empagliflozin is larger than 30 μm, so that the obtained sample has poor dissolution effect.
Claims (10)
1. The compound preparation of the empagliflozin and the metformin hydrochloride is characterized by comprising empagliflozin particles and metformin hydrochloride particles; the engelet granules comprise engelet, polacrilin potassium, maltose-cyclodextrin, a disintegrating agent and a binding agent; the metformin hydrochloride granules comprise metformin hydrochloride, a diluent, a disintegrant and a binder; wherein the particle size d0.9 of the empagliflozin is not more than 30 μm.
2. The compound preparation of empagliflozin hydrochloride and metformin hydrochloride according to claim 1, wherein the mass dosage ratio of the polacrilin potassium to the maltose-cyclodextrin is 1-5: 1.
3. The compound preparation of empagliflozin hydrochloride and metformin hydrochloride according to claim 1, characterized in that the disintegrant is one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium.
4. The compound preparation of empagliflozin hydrochloride and metformin hydrochloride according to claim 1, characterized in that the binder is one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose and povidone.
5. The compound formulation of empagliflozin and metformin hydrochloride according to claim 1, characterized in that the empagliflozin particles further comprise a diluent.
6. The compound formulation of empagliflozin and metformin hydrochloride according to claim 1 or 5, wherein the diluent is one or more of microcrystalline cellulose, pregelatinized starch, lactose, dibasic calcium phosphate, sorbitol, starch and sucrose.
7. The compound formulation of empagliflozin and metformin hydrochloride according to claim 1, characterized in that the empagliflozin particles and/or metformin hydrochloride particles further comprise a lubricant.
8. The compound preparation of empagliflozin hydrochloride and metformin hydrochloride according to claim 7, wherein the lubricant is one or more of magnesium stearate, aerosil and talcum powder.
9. The compound preparation of empagliflozin hydrochloride and metformin hydrochloride according to claim 1, characterized in that the compound preparation comprises the following components in parts by mass:
the engelet granule comprises 5-12.5 parts of engelet, 30-70 parts of polacrilin potassium, 10-30 parts of maltose-cyclodextrin, 2-5 parts of disintegrant and 2-5 parts of adhesive;
the metformin hydrochloride particles comprise 1000 parts of metformin hydrochloride 500-plus, 24-50 parts of diluent, 20-50 parts of disintegrant and 6-18 parts of adhesive;
wherein the dosage of the metformin hydrochloride is calculated by metformin.
10. A method for preparing the compound preparation of the empagliflozin hydrochloride and the metformin hydrochloride according to claim 1, which comprises the following steps:
(1) uniformly mixing the engletin, the polacrilin potassium, the maltose-cyclodextrin, the disintegrating agent and the adhesive, granulating by a wet method, and drying to obtain engletin granules;
(2) uniformly mixing metformin hydrochloride, a diluent, a disintegrating agent and an adhesive, performing wet granulation, and drying to obtain metformin hydrochloride granules;
(3) the empagliflozin particles and the metformin hydrochloride particles are uniformly mixed and tabletted.
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| EP4342459A1 (en) * | 2022-09-20 | 2024-03-27 | Galenicum Health S.L.U. | Pharmaceutical compositions of empagliflozin |
| EP4378455A1 (en) * | 2022-11-29 | 2024-06-05 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A pharmaceutical formulation comprising empagliflozin |
| WO2024128996A1 (en) * | 2022-12-16 | 2024-06-20 | Santa Farma Ilac Sanayii A.S. | Monolayer tablet composition of empagliflozin and metformin hydrochloride |
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| US20100029721A1 (en) * | 2006-09-29 | 2010-02-04 | Novo Nordisk A/S | Pharmaceutical Formulation Comprising Metformin and Repaglinide |
| WO2020058095A1 (en) * | 2018-09-19 | 2020-03-26 | Galenicum Health S.L.U. | Pharmaceutical compositions of empagliflozin |
| WO2021123165A1 (en) * | 2019-12-19 | 2021-06-24 | Krka, D.D., Novo Mesto | Dosage form comprising amorphous solid solution of empagliflozin with polymer |
| KR20210084053A (en) * | 2019-12-27 | 2021-07-07 | (주)휴온스 | Pharmaceutical composite formulation comprising empagliflozin and metformin and method for manufacturing the same |
| CN113855638A (en) * | 2021-10-28 | 2021-12-31 | 北京福元医药股份有限公司 | Rosemastat pharmaceutical preparation |
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| US20100029721A1 (en) * | 2006-09-29 | 2010-02-04 | Novo Nordisk A/S | Pharmaceutical Formulation Comprising Metformin and Repaglinide |
| WO2020058095A1 (en) * | 2018-09-19 | 2020-03-26 | Galenicum Health S.L.U. | Pharmaceutical compositions of empagliflozin |
| WO2021123165A1 (en) * | 2019-12-19 | 2021-06-24 | Krka, D.D., Novo Mesto | Dosage form comprising amorphous solid solution of empagliflozin with polymer |
| KR20210084053A (en) * | 2019-12-27 | 2021-07-07 | (주)휴온스 | Pharmaceutical composite formulation comprising empagliflozin and metformin and method for manufacturing the same |
| CN113855638A (en) * | 2021-10-28 | 2021-12-31 | 北京福元医药股份有限公司 | Rosemastat pharmaceutical preparation |
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| EP4342459A1 (en) * | 2022-09-20 | 2024-03-27 | Galenicum Health S.L.U. | Pharmaceutical compositions of empagliflozin |
| EP4378455A1 (en) * | 2022-11-29 | 2024-06-05 | Sanovel Ilac Sanayi Ve Ticaret A.S. | A pharmaceutical formulation comprising empagliflozin |
| WO2024128996A1 (en) * | 2022-12-16 | 2024-06-20 | Santa Farma Ilac Sanayii A.S. | Monolayer tablet composition of empagliflozin and metformin hydrochloride |
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